Development of proteoglycan-induced arthritis depends on T cell-supported autoantibody production, but does not involve significant influx of T cells into the joints
Development of proteoglycan-induced arthritis depends on T cell-supported autoantibody production, but does not involve significant influx of T cells into the joints
复制标题
DOI：
10.1186/ar2954
复制
发表时间：
2010-01-01
影响因子：
4.9
通讯作者：
Mikecz, Katalin
中科院分区：
文献类型：
--
作者：
Angyal, Adrienn;Egelston, Colt;Mikecz, Katalin
简介：类风湿性关节炎 (RA) 中的炎症性关节破坏可能是由自身抗体引发的，自身抗体的产生由自身反应性 T 细胞支持。对 RA 和该疾病动物模型的研究表明，关节中募集的 T 细胞可以局部引发或传播关节炎。在此，我们研究了关节归巢 T 细胞与淋巴器官归巢 T 细胞在蛋白聚糖诱导关节炎 (PGIA)（一种 RA 自身免疫模型）发展中的作用。方法：为了鉴定在自身免疫性关节炎发展之前和发展过程中迁移到关节的 T 细胞，我们将荧光标记的 T 细胞以及抗原呈递细胞从患有 PGIA 的 BALB/c 小鼠转移到幼稚同系严重联合免疫缺陷 (SCID) 小鼠中。然后，我们使用体内双光子显微镜和离体检测方法监测受体踝关节和关节引流淋巴结中供体 T 细胞的募集情况。为了限制 T 细胞进入关节，我们通过 FTY720（一种淋巴细胞从淋巴器官流出的抑制剂）治疗选择性地耗尽血液循环中的 T 细胞。通过注射在移植前去除 T 细胞的供体细胞，可以减少淋巴器官和血液中 T 细胞的存在。通过流式细胞术对 T 细胞和 B 细胞进行定量，并通过细胞增殖和血清抗体测定来评估抗原 (PG) 特异性反应。 结果：尽管受者 SCID 小鼠出现过继性转移性关节炎，但我们在细胞转移后发现其关节中的供体 T 细胞很少。用 FTY720 治疗受体小鼠后，淋巴器官中的 T 细胞库保持完整，但外周血和关节中的 T 细胞减少。然而，FTY720 治疗未能抑制 PGIA 的发展。相比之下，从关节炎供体移植 T 细胞耗尽的细胞后，受体小鼠中没有发现关节炎，并且在这组小鼠中没有检测到针对 PG 的血清自身抗体。结论：我们的结果表明，抗原特异性 T 细胞归巢于淋巴器官，并为 B 细胞提供系统性自身抗体产生的帮助，在自身免疫性关节炎的发生和进展中比迁移到关节的小群 T 细胞发挥更大的作用。
Introduction: Inflammatory joint destruction in rheumatoid arthritis (RA) may be triggered by autoantibodies, the production of which is supported by autoreactive T cells. Studies on RA and animal models of the disease suggest that T cells recruited in the joints can locally initiate or propagate arthritis. Herein, we investigated the role of joint-homing versus lymphoid organ-homing T cells in the development of proteoglycan-induced arthritis (PGIA), an autoimmune model of RA.Methods: To identify T cells migrating to the joints before and during development of autoimmune arthritis, we transferred fluorescence-labeled T cells, along with antigen-presenting cells, from BALB/c mice with PGIA to naive syngeneic severe combined immunodeficient (SCID) mice. We then monitored the recruitment of donor T cells in the ankle joints and joint-draining lymph nodes of the recipients using in vivo two-photon microscopy and ex vivo detection methods. To limit T-cell access to the joints, we selectively depleted T cells in the blood circulation by treatment with FTY720, an inhibitor of lymphocyte egress from lymphoid organs. Reduction of T cell presence in both lymphoid organs and blood was achieved by injection of donor cells from which T cells were removed prior to transfer. T and B cells were quantitated by flow cytometry, and antigen (PG)-specific responses were assessed by cell proliferation and serum antibody assays.Results: Despite development of adoptively transferred arthritis in the recipient SCID mice, we found very few donor T cells in their joints after cell transfer. Treatment of recipient mice with FTY720 left the T-cell pool in the lymphoid organs intact, but reduced T cells in both peripheral blood and joints. However, FTY720 treatment failed to inhibit PGIA development. In contrast, arthritis was not seen in recipient mice after transfer of T cell-depleted cells from arthritic donors, and serum autoantibodies to PG were not detected in this group of mice.Conclusions: Our results suggest that antigen-specific T cells, which home to lymphoid organs and provide help to B cells for systemic autoantibody production, play a greater role in the development and progression of autoimmune arthritis than the small population of T cells that migrate to the joints.